Alternative Complement Pathway Activation Is Essential for Inflammation and Joint Destruction in the Passive Transfer Model of Collagen-Induced Arthritis

Abstract

Activation of each complement initiation pathway (classical, alternative, and lectin) can lead to the generation of bioactive fragments with resulting inflammation in target organs. The objective of the current study was to determine the role of specific complement activation pathways in the pathogenesis of experimental anti-type II collagen mAb-passive transfer arthritis. C57BL/6 mice were used that were genetically deficient in either the alternative pathway protein factor B (Bf−/−) or in the classical pathway component C4 (C4−/−). Clinical disease activity was markedly decreased in Bf−/− compared with wild-type (WT) mice (0.5 ± 0.22 (n = 6) in Bf−/− vs 8.83 ± 0.41 (n = 6) in WT mice (p < 0.0001)). Disease activity scores were not different between C4−/− and WT mice. Analyses of joints showed that C3 deposition, inflammation, pannus, cartilage, and bone damage scores were all significantly less in Bf−/− as compared with WT mice. There were significant decreases in mRNA levels of C3, C4, CR2, CR3, C3aR, and C5aR in the knees of Bf−/− as compared with C4−/− and WT mice with arthritis; mRNA levels for complement regulatory proteins did not differ between the three strains. These results indicate that the alternative pathway is absolutely required for the induction of arthritis following injection of anti-collagen Abs. The mechanisms by which these target organ-specific mAbs bypass the requirements for engagement of the classical pathway remain to be defined but do not appear to involve a lack of alternative pathway regulatory proteins.

Anti–cyclic citrullinated peptide antibodies from rheumatoid arthritis patients activate complement via both the classical and alternative pathways

“…In mouse models of arthritis clear evidence has been provided that the alternative pathway in particular, and not the classical pathway, is responsible for organ damage, based on experiments using complementdeficient animals (25,27) or a specific alternative pathway inhibitor (26). The present study provides evidence that human anti-CCP antibodies activate both the classical pathway and the alternative pathway and thereby mimic the results obtained from in vivo models.…”

“…C3 Ϫ/Ϫ , FB Ϫ/Ϫ , C5 Ϫ/Ϫ , and C5a receptor Ϫ/Ϫ mice are protected against induction of arthritis, whereas C1q Ϫ/Ϫ and MBL Ϫ/Ϫ mice are fully susceptible (25,26), indicating that in mouse models the alternative pathway is necessary and sufficient for disease induction (25,27,28). Now that ACPAs are increasingly recognized as major players in RA, it is of relevance to know if and how these antibodies activate complement.…”

The Alternative Pathway of Complement Activation Is Critical for Blister Induction in Experimental Epidermolysis Bullosa Acquisita

“…Ϫ/Ϫ mice does not abolish the pathogenic effects of K/BxNderived anti-GPI serum or of anti-collagen II Abs in a passive transfer model of rheumatoid arthritis (24,31). Fetal loss and growth restriction triggered by anti-cardiolipin Abs in mice, main features of the antiphospholipid syndrome, and blistering induced by Abs against BP180 in experimental bullous pemphigoid also depend on complement activation (28,32,33).…”

The major risk alleles of age-related macular degeneration (AMD) in CFH do not play a major role in rheumatoid arthritis (RA)

“…However, antibodies directed against citrullinated proteins (ACPA) are associated strongly with RA; they can be detected years before disease onset and are a risk factor for severe damage to the joints [12]. Mouse models of arthritis that use arthritogenic antibodies show that the pathogenicity of these antibodies depends on the AP of complement [13][14][15]. Interestingly, in the human situation, RA-associated antibodies, ACPA, also display a strong capacity to activate AP [16].…”